Endothelial injury sets in process a chain of events that disrupt vascular homeostasis and promote atherosclerosis. Until recently, it was believed that the endogenous capacity to repair or regenerate damaged endothelium was limited. It is now known that the adult peripheral blood contains a population of endothelial progenitor cells (EPCs) that contribute to vascular repair and re-endothelialization. Early clinical studies raise the possibility that EPCs could serve as a novel biomarker of cardiovascular disease (CVD) risk, but these studies were limited by small sample sizes and lack of longitudinal follow up. We postulate that susceptibility to CVDis determined by the balance between endothelial injury, mediated byCVD risk factors, and endothelialrepair, in part determined by EPCs. We propose to test the following hypotheses: (1)'EPC number and function decline with advancing age, and are related to life-long exposure to known CVD risk factors;(2) genetic variation influences EPC measures;(3) reduced EPC number and function are associated with subclinical vascular structural and functional alterations cross-sectionally;and (4) reduced EPC number and function predispose to the development of CVD longitudinally, above and beyond traditional risk factors. We propose to assess EPCs in a large, prospective cohort (approximately 3500 Framingham Heart Study [FHS] participants at Offspring exam 8 and Omni exam 3). Our specific aims are: (1) To examine the clinical and genetic correlates of EPC number and function (using in vitro colony counts, flow cytometry,-migratory assays, and (3-galactosidase staining);(2) To investigate the association of EPC characteristics with subclinical measures of vascular structure (carotid intima-media thickness [IMT], carotid stenosis) and function (peripheral arterial tonometry, brachial flow-mediated dilation, vascular tonometry);and (3) To analyze the relations of EPC characteristics with prevalent and incident CVD. The proposed research represents a collaboration between investigators at the FHS, Massachusetts General Hospital (MGH) Cardiology Division, and MGH Center for Regenerative Medicine. The FHS cohort provides a large, single site, community-based sample of middle-aged and elderly individuals who have been extensively characterized over 3 decades and are under continuous surveillance for new CVD events. The combination of investigator expertise and a well-phenotyped cohort should allow rigorous examination of the relations between endothelial repair, subclinical CVD, and CVD risk. Abnormalities in the body's ability to repair damaged blood vessels may contribute to the risk of heart disease and stroke. If this hypothesis is true, then examination of the circulating "repair" cells in the blood, known as endothelial progenitor cells, may provide insight into an individual's susceptibility to cardiovascular disease and may suggest novel therapeutic approaches.